Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53

Bache, Matthias; Pigorsch, Steffi; Dunst, Jürgen; Würl, Peter; Meye, Axel; Bartel, Frank; Schmidt, Harald; Rath, Friedrich-Wilhelm; Täubert, Helge

doi:10.1002/ijc.1002

Cited by 41 publications

(27 citation statements)

References 33 publications

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“…Increased radiation resistance with a prolonged arrest in G 2 /M was documented (39). Conversely, acceleration of G 2 /M transition resulted in radiosensitization of cells (40,41). In this study, we found that 5-125 enhanced γ-irradiation-induced accumulation of the G 2 /M population and prolonged the G 2 /M phase arrest with either preirradiation or postirradiation treatment.…”

Section: Discussionmentioning

confidence: 99%

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang¹,

Belikova²,

Hoye³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To evaluate the in vitro radioprotective effect of the mitochondria-targeted hemigramicidin S-conjugated 4-amino-2,2,6,6-tetramethyl-piperidine-N-oxyl (hemi-GS-TEMPO) 5-125 in γ-irradiated mouse embryonic cells and adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells BEAS-2B and explore the mechanisms involved in its radioprotective effect.Methods and Materials-Cells were incubated with 5-125 before (10 minutes) or after (1 hour) γ-irradiation. Superoxide generation was determined by using dihydroethidium assay, and lipid oxidation was quantitated by using a fluorescence high-performance liquid chromatography-based Amplex Red assay. Apoptosis was characterized by evaluating the accumulation of cytochrome c in the cytosol and externalization of phosphatidylserine on the cell surface. Cell survival was measured by means of a clonogenic assay.Results-Treatment (before and after irradiation) of cells with 5-125 at low concentrations (5, 10, and 20 μM) effectively suppressed γ-irradiation-induced superoxide generation, cardiolipin oxidation, and delayed irradiation-induced apoptosis, evaluated by using cytochrome c release and phosphatidylserine externalization. Importantly, treatment with 5-125 increased the clonogenic survival rate of γ-irradiated cells. In addition, 5-125 enhanced and prolonged γ-irradiation-induced G 2 /M phase arrest.Conclusions-Radioprotection/mitigation by hemi-GS-TEMPO likely is caused by its ability to act as an electron scavenger and prevent superoxide generation, attenuate cardiolipin oxidation in mitochondria, and hence prevent the release of proapoptotic factors from mitochondria. Other mechanisms, including cell-cycle arrest at the G 2 /M phase, may contribute to the protection.

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Section: Discussionmentioning

confidence: 99%

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang¹,

Belikova²,

Hoye³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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“…For sensitization to cell killing in tumor cells and tissues exposed to ionizing radiation, treatments combined with a pharmacological agent with the ability to abrogate the G 2 /M checkpoint have been of interest. UCN-01 and caffeine have been shown to be able to enhance radiation-induced cell killing by inhibition of kinases such as ATM, ataxia telangiectasia mutated and RAD3-related (ATR), and CHK1 exists in the upstream of CDC2 (15)(16)(17)(18). Palayoor et al examined the effects of several xanthine derivatives on the radiation-induced G 2 /M checkpoint and apoptosis and found that caffeine, theobromine, theophylline and 2-aminopurine abrogated the checkpoint and enhanced the degree of apoptosis in EL4 murine T-lymphoma cells (19).…”

Section: Discussionmentioning

confidence: 99%

Purvalanol A Enhances Cell Killing by Inhibiting Up-Regulation of CDC2 Kinase Activity in Tumor Cells Irradiated with High Doses of X Rays

et al. 2007

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“…It was reported by many studies that p53 lacking cells, including HL-60 cells, react to DNAdamaging factors (such as e.g. ionizing radiation or topoisomerase II inhibitors) preferentially by arrest of cell cycle in G2/M phase, which is followed by apoptosis induction (2,15,27,31,32,(36)(37)(38). This was not observed after 2-DG treatment, indicating that direct damage to DNA is not responsible for the antitumor effect of 2-DG.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Antineoplastic Activity of L-rhamnose in vitro. A Comparison with 2-deoxyglucose

Tomšík

Stoklasová

Mičuda

et al. 2008

Acta Med. (Hradec Kralove, Czech Repub.)

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IntroductionIn the last decades, the possible effects of unsubstituted deoxyhexoses on tumor cells and their use in cancer treatment have been discussed. Above all, 2-deoxy-D-glucose (2-DG) and L-fucose have been studied in numerous works both in vitro and in vivo. 2-Deoxyglucose is a synthetic glucose analogue that inhibits phospho-hexose isomerase in the initial stage of glycolysis (29,33) and induces glucoseregulated stress affecting tumor cells in particular (9, 42). The inhibitory effect of 2-DG on tumor growth has been reported in both in vitro (43) and in vivo (5, 10) studies. Glycolysis inhibition and resulting energy depletion trigger apoptotic cell death. The mechanisms include inhibition of phosphatidylinositol 3-kinase/Akt signaling (35), increased production of reactive oxygen species, interference with MAPK pathways and stabilization of p53 (19). Corresponding to this, 2-DG was found to induce cell death by the activation of apoptosis (1). Regardless of the mechanism which triggers apoptosis by either intrinsic (mitochondrial) or extrinsic (receptor) pathways, the apoptotic cells can be recognized by specific morphological changes: membrane blebbing, condensation, fragmentation of nuclear DNA, cleavage of nuclear proteins (e.g. lamin B) and formation of apoptotic bodies.L-fucose (6-deoxy-L-galactose) is the only endogenous deoxyhexose known in humans. Although a research group reported the effect of intravenously administered L-fucose on the size of a rat solid mammary adenocarcinoma in vivo (25, 41) as well as the efficacy of this deoxysugar in vitro (21,24,28,40), no significant cytostatic potency of single L-fucose in vitro or L-fucose monotherapy has been confirmed in the recent literature. However, it has been noted that L-fucose enhances the cytolytic activity of immune system effector cells and the production of cytokines like interleukin 2 and tumor necrosis factor α (30). It is well documented that altered fucosylation plays an important role in the pathogenesis of malignant tumors (3,11,12). A potential antimetastatic effect of L-fucose and L-fucose containing oligosaccharides was reported as well (26).In nature, there is another deoxyhexose -L-rhamnose (6-deoxy-L-mannose) -similar to deoxyglucose. It is synthesized largely in plants and bacteria but not in animal cells (7). Since L-rhamnose can serve as substrate for L-fucose kinase (8), which catalyzes the first step in the salvage pathway for GDP-fucose biosynthesis (3), a hypothesis can be formulated that L-rhamnose could influence the fucosylation and thereby the behavior of tumor cells. The fact that L-rhamnose can be converted into glycosides in mammalian cells has been indeed evidenced by sporadic discoveries of rhamnosides in mammals (14, 34). Moreover, L-rhamnose, which penetrates by non-mediated diffusion into the cells (4), may be partially metabolized or join some human metabolic pathways (6,13 Summary: The effect of unsubstituted deoxyhexoses, 2-deoxy-D-glucose (2-DG) and L-fucose, on tumor cells has been reported in several...

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Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53

Cited by 41 publications

References 33 publications

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Purvalanol A Enhances Cell Killing by Inhibiting Up-Regulation of CDC2 Kinase Activity in Tumor Cells Irradiated with High Doses of X Rays

Evaluation of the Antineoplastic Activity of L-rhamnose in vitro. A Comparison with 2-deoxyglucose

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